Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fastin...Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.展开更多
BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been i...BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been identified.Mitochondrial dysfunction,oxidative stress,inflammation,and calcium handling imbalance play a crucial role in the pathological processes of DCM,ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions.Empagliflozin,a novel glucoselowering agent,has been confirmed to reduce the risk of hospitalization for HF in diabetic patients.Nevertheless,the molecular mechanisms by which this agent provides cardioprotection remain unclear.AIM To investigate the effects of empagliflozin on high glucose(HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG(30 mmol/L)were separately employed as in vivo and in vitro models.Echocardiography was used to evaluate cardiac function.Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells.Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential.Furthermore,intracellular reactive oxygen species production and superoxide dismutase activity were analyzed.Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression.Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase(AMPK)and myosin phosphatase target subunit 1(MYPT1),as well as the peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)and active caspase-3 protein levels.RESULTSIn the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin(10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis,accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease inthe phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment ofcardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis.However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG,empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylatedMYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressingPGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucosecotransporter (SGLT)2 protein expression was detected in cardiomyocytes.CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HGconditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.展开更多
BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease.However,the mechanisms unde...BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease.However,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice.METHODS We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 wk.Age-matched male db/+mice were included as non-diabetic controls.Parameters of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were assessed.We evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,respectively.Glomerular nephrin and transforming growth factor beta(TGF-β)were assessed by immunohistochemistry.RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were detected.Mesangial expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated mice.Podocytopathy was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were reduced.EMPA decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of nephrin.CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease.The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.展开更多
BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities.There are no case reports about association of Em...BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities.There are no case reports about association of Empagliflozin with finger ulcers or gangrene.This is the first case report of Empagliflozin(Jardiance)an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity.CASE SUMMARY A 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers,which started healing.He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months.Investigations were negative for vascular insufficiency,infection and vasculitis and imaging of hand was normal.Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain.CONCLUSION This case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.展开更多
<strong>Background:</strong> <span style="font-family:;" "=""><span style="font-family:Verdana;">A selective inhibitor of sodium-glucose cotransporter 2 (SGLT...<strong>Background:</strong> <span style="font-family:;" "=""><span style="font-family:Verdana;">A selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), empagliflozin, has demonstrated its effects in reducing cardiovascular mortality and hospitalization rates for heart failure in type 2 diabetes patients. However, the cardiac-intrinsic mechanism for this cardiovascular benefit has not been sufficiently studied. We therefore aimed to investigate the effect of empagliflozin on left ventricular function in a group of patients with grade I hypertension. </span><b><span style="font-family:Verdana;">Methods:</span></b><span style="font-family:Verdana;"> We carried out a single-arm non-randomized clinical trial at the National Obesity Centre in Yaoundé over a period </span></span><span style="font-family:Verdana;">of </span><span style="font-family:Verdana;">8 months (October 2016 to May 2017), where patients were assigned to receive 25</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">mg of empagliflozin once daily. Cardiac ultrasound, 24</span><span style="font-family:Verdana;">-</span><span style="font-family:;" "=""><span style="font-family:Verdana;">hour ambulatory blood pressure measurement, resting electrocardiography and biological assessment were carried out at baseline and at the end of a 6-week treatment period with empagliflozin. The primary outcome was the improvement of the left ventricular relaxation evaluation criteria. Ethical approval was obtained from the Centre Regional Ethics Committee in Yaoundé, Cameroon. </span><b><span style="font-family:Verdana;">Results: </span></b><span style="font-family:Verdana;">A total of 11 patients were treated (median observation time, 6 weeks). We noted a non-significant improvement in the early lateral annular velocity from 9.7 [9.2</span></span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">11.4] cm/s to 9.1 [8.8</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">10.2] cm/s, p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:;" "=""></span><span style="font-family:Verdana;">0.21. We also noted a non-significant improvement of the mitral profile (E/A) from 0.71 [0.63</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.78] cm/s to 0.81 [0.58</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.88] cm/s,</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">= 0.08. There were no differences in E/E’ ratio, 5.0 [4.1</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">6.3] vs 5.6 [4.9</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">7.4], p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.07. There was a non-significant</span><span style="font-family:Verdana;"> drop in both systolic (p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.06) and diastolic (p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.09) blood pressure. We also observed on ECG a drop of the PR interval from 200 [157</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">- 200] ms to 160 [143</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">186] ms, p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">0.04. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> Short-term treatment with empagliflozin does not show an improvement of the left ventricular function </span></span><span style="font-family:;" "=""><span style="font-family:Verdana;">in grade I hypertensive patients with diastolic dysfunction. </span><b><span style="font-family:Verdana;">Trial registration:</span></b><span style="font-family:Verdana;"> This </span></span><span style="font-family:Verdana;">study was retrospectively registered on Clinical Trial Registry with ClinicalTrials.gov Identifier: NCT04203914.</span>展开更多
Sodium-glucose cotransporter 2(SGLT2)inhibitors have been reapproved for heart failure(HF)therapy in patients with and without diabetes.However,the initial glucose-lowering indication of SGLT2i has impeded their uses ...Sodium-glucose cotransporter 2(SGLT2)inhibitors have been reapproved for heart failure(HF)therapy in patients with and without diabetes.However,the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice.A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect.To address this issue,we conducted structural repurposing of EMPA,a representative SGLT2 inhibitor,to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2.Compared to EMPA,the optimal derivative JX01,which was produced by methylation of C2—OH of the glucose ring,exhibited weaker SGLT2-inhibitory activity(IC_(50)>100 nmol/L),and lower glycosuria and glucose-lowering side-effect,better NHE1-inhibitory activity and cardioprotective effect in HF mice.Furthermore,JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity,and good pharmacokinetic properties in both mouse and rat species.Collectively,the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs,and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.展开更多
BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCT...BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.展开更多
Sodium-glucose cotransporter-2(SGLT2)inhibitors have emerged as a pivotal intervention in diabetes management,offering significant cardiovascular benefits.Empagliflozin,in particular,has demonstrated cardioprotective ...Sodium-glucose cotransporter-2(SGLT2)inhibitors have emerged as a pivotal intervention in diabetes management,offering significant cardiovascular benefits.Empagliflozin,in particular,has demonstrated cardioprotective effects beyond its glucose-lowering action,reducing heart failure hospitalizations and improving cardiac function.Of note,the cardioprotective mechanisms appear to be independent of glucose lowering,possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic,anti-inflammatory,and anti-oxidative pathways.This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors,highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.展开更多
目的:探讨二甲双胍恩格列净片治疗2型糖尿病(T2DM)合并射血分数保留性心力衰竭(HFpEF)患者的临床效果和安全性。方法:选取2021年10月—2022年9月保定市第一中心医院80例T2DM合并HFpEF患者,通过随机数字表法将其分为观察组(n=40)和对照组...目的:探讨二甲双胍恩格列净片治疗2型糖尿病(T2DM)合并射血分数保留性心力衰竭(HFpEF)患者的临床效果和安全性。方法:选取2021年10月—2022年9月保定市第一中心医院80例T2DM合并HFpEF患者,通过随机数字表法将其分为观察组(n=40)和对照组(n=40)。对照组给予常规药物治疗,观察组在对照组的用药基础上联合二甲双胍恩格列净片治疗。两组均接受为期6个月的连续治疗。对比两组血糖指标、心功能指标及不良反应发生情况。结果:治疗后,两组空腹血糖(FBG)、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1c)均较治疗前下降,且观察组均低于对照组(P<0.05)。治疗后,两组左室射血分数(LVEF)、左室舒张末径(LVEDD)、左室收缩末径(LVESD)、脑钠肽(BNP)均优于治疗前,且观察组均优于对照组(P<0.05)。观察组不良反应发生率(5.0%)低于对照组(22.5%),差异有统计学意义(P<0.05)。结论:二甲双胍恩格列净片治疗2型糖尿病合并HFpEF临床效果显著,能够使患者的血糖水平下降并提高心功能相关指标,同时安全性较高。展开更多
文摘Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.
基金Health Commission of Hebei Province,No.20210196S&T Program of Hebei,No.22377726D。
文摘BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been identified.Mitochondrial dysfunction,oxidative stress,inflammation,and calcium handling imbalance play a crucial role in the pathological processes of DCM,ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions.Empagliflozin,a novel glucoselowering agent,has been confirmed to reduce the risk of hospitalization for HF in diabetic patients.Nevertheless,the molecular mechanisms by which this agent provides cardioprotection remain unclear.AIM To investigate the effects of empagliflozin on high glucose(HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG(30 mmol/L)were separately employed as in vivo and in vitro models.Echocardiography was used to evaluate cardiac function.Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells.Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential.Furthermore,intracellular reactive oxygen species production and superoxide dismutase activity were analyzed.Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression.Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase(AMPK)and myosin phosphatase target subunit 1(MYPT1),as well as the peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)and active caspase-3 protein levels.RESULTSIn the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin(10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis,accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease inthe phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment ofcardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis.However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG,empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylatedMYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressingPGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucosecotransporter (SGLT)2 protein expression was detected in cardiomyocytes.CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HGconditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
基金Supported by Ministry of Science and Higher Education of Russia(the budget projects No.0324-2019-0045/0324-2019-0045-C-02,grant No.RFMEFI62119X0023)Boehringer Ingelheim Pharma。
文摘BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease.However,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice.METHODS We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 wk.Age-matched male db/+mice were included as non-diabetic controls.Parameters of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were assessed.We evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,respectively.Glomerular nephrin and transforming growth factor beta(TGF-β)were assessed by immunohistochemistry.RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were detected.Mesangial expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated mice.Podocytopathy was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were reduced.EMPA decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of nephrin.CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease.The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.
文摘BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities.There are no case reports about association of Empagliflozin with finger ulcers or gangrene.This is the first case report of Empagliflozin(Jardiance)an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity.CASE SUMMARY A 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers,which started healing.He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months.Investigations were negative for vascular insufficiency,infection and vasculitis and imaging of hand was normal.Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain.CONCLUSION This case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.
文摘<strong>Background:</strong> <span style="font-family:;" "=""><span style="font-family:Verdana;">A selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), empagliflozin, has demonstrated its effects in reducing cardiovascular mortality and hospitalization rates for heart failure in type 2 diabetes patients. However, the cardiac-intrinsic mechanism for this cardiovascular benefit has not been sufficiently studied. We therefore aimed to investigate the effect of empagliflozin on left ventricular function in a group of patients with grade I hypertension. </span><b><span style="font-family:Verdana;">Methods:</span></b><span style="font-family:Verdana;"> We carried out a single-arm non-randomized clinical trial at the National Obesity Centre in Yaoundé over a period </span></span><span style="font-family:Verdana;">of </span><span style="font-family:Verdana;">8 months (October 2016 to May 2017), where patients were assigned to receive 25</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">mg of empagliflozin once daily. Cardiac ultrasound, 24</span><span style="font-family:Verdana;">-</span><span style="font-family:;" "=""><span style="font-family:Verdana;">hour ambulatory blood pressure measurement, resting electrocardiography and biological assessment were carried out at baseline and at the end of a 6-week treatment period with empagliflozin. The primary outcome was the improvement of the left ventricular relaxation evaluation criteria. Ethical approval was obtained from the Centre Regional Ethics Committee in Yaoundé, Cameroon. </span><b><span style="font-family:Verdana;">Results: </span></b><span style="font-family:Verdana;">A total of 11 patients were treated (median observation time, 6 weeks). We noted a non-significant improvement in the early lateral annular velocity from 9.7 [9.2</span></span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">11.4] cm/s to 9.1 [8.8</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">10.2] cm/s, p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:;" "=""></span><span style="font-family:Verdana;">0.21. We also noted a non-significant improvement of the mitral profile (E/A) from 0.71 [0.63</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.78] cm/s to 0.81 [0.58</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.88] cm/s,</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">= 0.08. There were no differences in E/E’ ratio, 5.0 [4.1</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">6.3] vs 5.6 [4.9</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">7.4], p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.07. There was a non-significant</span><span style="font-family:Verdana;"> drop in both systolic (p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.06) and diastolic (p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">0.09) blood pressure. We also observed on ECG a drop of the PR interval from 200 [157</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">- 200] ms to 160 [143</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">-</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">186] ms, p</span><span style="font-family:Verdana;"> </span><span style="font-family:Verdana;">=</span><span style="font-family:Verdana;"> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">0.04. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> Short-term treatment with empagliflozin does not show an improvement of the left ventricular function </span></span><span style="font-family:;" "=""><span style="font-family:Verdana;">in grade I hypertensive patients with diastolic dysfunction. </span><b><span style="font-family:Verdana;">Trial registration:</span></b><span style="font-family:Verdana;"> This </span></span><span style="font-family:Verdana;">study was retrospectively registered on Clinical Trial Registry with ClinicalTrials.gov Identifier: NCT04203914.</span>
基金supported by the National key R&D Program of China(2021YFA0804904)the National Natural Science Foundation of China(22107030)+4 种基金the Chinese Postdoctoral Science Foundation(2020M681211)the Shanghai Morning Light Program(20CG36,China)the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism(2021 Sci&Tech 03-28,China)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212702,China)the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204)。
文摘Sodium-glucose cotransporter 2(SGLT2)inhibitors have been reapproved for heart failure(HF)therapy in patients with and without diabetes.However,the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice.A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect.To address this issue,we conducted structural repurposing of EMPA,a representative SGLT2 inhibitor,to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2.Compared to EMPA,the optimal derivative JX01,which was produced by methylation of C2—OH of the glucose ring,exhibited weaker SGLT2-inhibitory activity(IC_(50)>100 nmol/L),and lower glycosuria and glucose-lowering side-effect,better NHE1-inhibitory activity and cardioprotective effect in HF mice.Furthermore,JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity,and good pharmacokinetic properties in both mouse and rat species.Collectively,the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs,and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.
文摘BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.
文摘Sodium-glucose cotransporter-2(SGLT2)inhibitors have emerged as a pivotal intervention in diabetes management,offering significant cardiovascular benefits.Empagliflozin,in particular,has demonstrated cardioprotective effects beyond its glucose-lowering action,reducing heart failure hospitalizations and improving cardiac function.Of note,the cardioprotective mechanisms appear to be independent of glucose lowering,possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic,anti-inflammatory,and anti-oxidative pathways.This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors,highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.
文摘目的:探讨二甲双胍恩格列净片治疗2型糖尿病(T2DM)合并射血分数保留性心力衰竭(HFpEF)患者的临床效果和安全性。方法:选取2021年10月—2022年9月保定市第一中心医院80例T2DM合并HFpEF患者,通过随机数字表法将其分为观察组(n=40)和对照组(n=40)。对照组给予常规药物治疗,观察组在对照组的用药基础上联合二甲双胍恩格列净片治疗。两组均接受为期6个月的连续治疗。对比两组血糖指标、心功能指标及不良反应发生情况。结果:治疗后,两组空腹血糖(FBG)、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1c)均较治疗前下降,且观察组均低于对照组(P<0.05)。治疗后,两组左室射血分数(LVEF)、左室舒张末径(LVEDD)、左室收缩末径(LVESD)、脑钠肽(BNP)均优于治疗前,且观察组均优于对照组(P<0.05)。观察组不良反应发生率(5.0%)低于对照组(22.5%),差异有统计学意义(P<0.05)。结论:二甲双胍恩格列净片治疗2型糖尿病合并HFpEF临床效果显著,能够使患者的血糖水平下降并提高心功能相关指标,同时安全性较高。
